2008
DOI: 10.1038/cdd.2008.98
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Identification of PP2A as a crucial regulator of the NF-κB feedback loop: its inhibition by UVB turns NF-κB into a pro-apoptotic factor

Abstract: Although nuclear factor-jB (NF-jB) usually exerts anti-apoptotic activity, upon activation by interleukin-1 (IL-1) it enhances ultraviolet-B radiation (UVB)-induced apoptosis. This paradoxical effect is associated with NF-jB-dependent pronounced secretion of tumour necrosis factor-a (TNF) which activates TNF-R1 in an autocrine fashion to enhance UVB-induced apoptosis. We demonstrate that sustained TNF transcription in UVB þ IL-1-treated cells involves complete abrogation of the negative feedback loop of NF-jB … Show more

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Cited by 56 publications
(72 citation statements)
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“…PP2A has been previously shown to either facilitate or inhibit IKK-␤ phosphorylation (4, 27, 50). Barisic et al (4) showed that inhibition of PP2A resulted in persistent IL-1-mediated IKK-␤ phosphorylation, supporting negative regulation of IKK-␤ phosphorylation by PP2A (4). However, Kray et al (27) demonstrated that TNF-␣-induced degradation of IB was attenuated by OA, which supports positive regulation of IKK-␤ by PP2A and is consistent with our observation that inhibition of PP2A by OA decreases LPS-induced IKK-␤ phosphorylation (27).…”
Section: Discussionmentioning
confidence: 99%
“…PP2A has been previously shown to either facilitate or inhibit IKK-␤ phosphorylation (4, 27, 50). Barisic et al (4) showed that inhibition of PP2A resulted in persistent IL-1-mediated IKK-␤ phosphorylation, supporting negative regulation of IKK-␤ phosphorylation by PP2A (4). However, Kray et al (27) demonstrated that TNF-␣-induced degradation of IB was attenuated by OA, which supports positive regulation of IKK-␤ by PP2A and is consistent with our observation that inhibition of PP2A by OA decreases LPS-induced IKK-␤ phosphorylation (27).…”
Section: Discussionmentioning
confidence: 99%
“…PP2A can dephosphorylate and modulate the activity of IKKβ (42), one of two catalytic subunits of IKK. Dephosphorylated IKKβ protein can reduce the degradation of IκBα and eventually inhibit the nuclear translocation and activation of NF-κB (42). The data suggests that the Vpr-inhibited NF-κB activity may occur in part through a PP2A-mediated mechanism and eventually promote progression of cell cycle G2/M arrest.…”
Section: Discussionmentioning
confidence: 83%
“…Constitutive activity of the proto-oncogene Src, activates different survival pathways, some of them involving downstream NFB activation (reviewed in [1]; [2;3] We have recently reported co-stimulation of cells with IL-1 and UVB to result in complete inhibition of the negative regulatory feedback loop of NFB, being due to UVBinduced inhibition of the Ser/Thr phosphatase PP2Ac [7]. After ruling out a number of putative Src substrates to interfere with IB degradation [28][29][30][31][32][33][34] Ser/Thr phosphatase PP2A was found to be the critical component.…”
Section: Discussionmentioning
confidence: 99%
“…Recently we demonstrated a crucial role for the Ser/Thr phosphatase PP2A in enabling this feedback loop as it mediates dephosphorylation of IKK Ser177/181 following IL-1 stimulation, thereby allowing re-accumulation of IB, as a prerequisite for NFB termination [7;8]. Specific inhibition of the catalytic subunit of PP2A, PP2Ac, resulted in preservation of Ser177/181 phosphorylation of IKK, continuous downstream phosphorylation and, as a consequence, chronic degradation of newly synthesized IBthereby causing inhibition of the negative feedback loop, hence, sustained NFB activation [7].…”
Section: Introductionmentioning
confidence: 99%